Lessons learned in a decade: Medical-toxicological view of tattooing.

Tattooing has been part of the human culture for thousands of years, yet only in the past decades has it entered the mainstream of the society. With the rise in popularity, tattoos also gained attention among researchers, with the aim to better understand the health risks posed by their application. 'A medical-toxicological view of tattooing'-a work published in The Lancet almost a decade ago, resulted from the international collaboration of various experts in the field. Since then, much understanding has been achieved regarding adverse effects, treatment of complications, as well as their regulation for improving public health. Yet major knowledge gaps remain. This review article results from the Second International Conference on Tattoo Safety hosted by the German Federal Institute for Risk Assessment (BfR) and provides a glimpse from the medical-toxicological perspective, regulatory strategies and advances in the analysis of tattoo inks.

Efficacy of GalNAc C3 siRNAs in factor H-deficient mice with C3 glomerulopathy.

Complement alternative pathway (AP) dysregulation drives C3 glomerulopathy (C3G), a rare renal disorder characterized by glomerular C3 deposition and glomerular damage, for which no effective treatments are available. Blockade of complement C3 is emerging as a viable therapeutic option. In an earlier study we showed that SLN500, a small interfering RNA targeting liver C3 synthesis, was able to limit AP dysregulation and glomerular C3d deposits in mice with partial factor H (FH) deficiency (Cfh+/- mice). Here, we assessed the pharmacological effects of SLN501 - an optimized SLN500 version - in mice with complete FH deficiency (Cfh-/- mice) that exhibit a more severe C3G phenotype. SLN501 effectively prevented liver C3 synthesis, thus limiting AP dysregulation, glomerular C3d deposits and the development of ultrastructural alterations. These data provide firm evidence of the use of siRNA-mediated liver C3 gene silencing as a potential therapy for treating C3G patients with either partial or complete FH loss of function.

Contact allergies to dental materials in patients.

BACKGROUND: Concerns regarding contact allergies and intolerance reactions to dental materials are widespread among patients. Development of novel dental materials and less frequent amalgam use may alter sensitization profiles in patients with possible contact allergy. OBJECTIVES: To analyse current sensitization patterns to dental materials in patients with suspected contact allergy. METHODS: This retrospective, multicentre analysis from the Information Network of Departments of Dermatology (IVDK) selected participants from 169 834 people tested in 2005-2019 and registered with (i) an affected area of 'mouth' (and 'lips'/'perioral'), (ii) with the dental material in question belonging to one of three groups (dental filling materials, oral implants or dentures or equivalents) and (iii) with patch-testing done in parallel with the German baseline series, (dental) metal series and dental technician series. RESULTS: A total of 2730 of 169 834 tested patients met the inclusion criteria. The patients were predominantly women (81.2%) aged ≥ 40 years (92.8%). The sensitization rates with confirmed allergic contact stomatitis in women (n = 444) were highest for metals (nickel 28.6%, palladium 21.4%, amalgam 10.9%), (meth)acrylates [2-hydroxyethyl methacrylate (HEMA) 4.8%] and the substances propolis (6.8%) and 'balsam of Peru' (11.4%). The most relevant acrylates were HEMA, 2-hydroxypropyl methacrylate, methyl methacrylate, ethylene glycol dimethacrylate and pentaerythritol triacrylate. Few men were diagnosed with allergic contact stomatitis (n = 68); sensitization rates in men were highest for propolis (14.9%) and amalgam (13.6%). CONCLUSIONS: Allergic contact stomatitis to dental materials is rare. Patch testing should not only focus on metals such as nickel, palladium, amalgam and gold, but also (meth)acrylates and the natural substances propolis and 'balsam of Peru'.

Declining frequency of sensitization to fragrance mixes I and II: IVDK-data of the years 2012-2021.

BACKGROUND: EU Commission Regulation 2017/1410 prohibits using atranol and chloroatranol, the main allergens in Evernia prunastri (oakmoss), and hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) in cosmetic products. Oakmoss absolute is contained in fragrance mix (FM) I and HICC in FM II which are patch tested as screening mixtures in the baseline series. OBJECTIVE: To describe the time trends of reaction frequencies to both FMs as well as to their components in FM-positive patients. METHODS: Retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), 2012-2021. RESULTS: Positive reactions to FM I (FM II) declined from 9.1% (4.7%) in 2012 to 4.6% (3.0%) in 2021. Full breakdown tests were performed in 24% (FM I) and 31% (FM II), respectively, of the mix-positive patients. From this data, frequencies of sensitization to the 14 single fragrances of FM I and FM II were calculated. For the majority, a decline was noted from 2012/2013 to 2020/2021, for oakmoss absolute 1.9%-0.8% and for HICC 1.8%-0.9%. CONCLUSION: EU Commission Regulation 2017/1410 was an effective measure. However, our data have some limitations, possibly causing underestimation of sensitization frequencies to fragrances.

Patch testing hydroperoxides of limonene and linalool in consecutive patients-Results of the IVDK 2018-2020.

BACKGROUND: Hydroperoxides of limonene (Lim-OOHs) and linalool (Lin-OOHs) are potent contact sensitizers. OBJECTIVES: To investigate the prevalence of positive patch test (PT) reactions to Lim-OOHs and Lin-OOHs in consecutive patients, their demographic factors and concomitant reactions. METHODS: Between 7/2018 and 12/2020, Lim-OOHs 0.3% pet. and Lin-OOHs 1% pet. were patch tested in 5511 consecutive patients. We assessed PT reactivity and analysed data from patients with either positive or negative PTs to Lim-OOHs and Lin-OOHs. RESULTS: Positive PT results to Lim-OOHs (n = 170, 3.1%) and Lin-OOHs (n = 483, 8.8%) were frequent. Most of the positive reactions were weak (LimOOHs n = 134/LinOOHs n = 429), and even more frequently, doubtful (n = 252/n = 578) or irritant reactions (n = 81/n = 178) were documented. PT reactivity to Lim-OOHs and Lin-OOHs was increased in patients with irritant reactions to sodium lauryl sulphate (SLS). The proportion of leg dermatitis and concomitant positive reactions to fragrances and essential oils was increased in patients with reactivity to these hydroperoxides. CONCLUSION: The observed reaction pattern suggests that both test preparations display an irritant potential with an increased risk of false positive reactions. Preparations should be chemically monitored in order to reduce irritancy. Mindful interpretation of PT results and aimed patch testing of lower concentrations is recommended.

Contact sensitization to benzisothiazolinone: IVDK-data of the years 2002 to 2021.

BACKGROUND: Benzisothiazolinone (BIT; CAS no. 2634-33-5) is used as a biocide in various products, including water-based paints, metalworking fluids, and household products. In recent years, increasing sensitization rates have been observed in Europe. OBJECTIVE: To describe a time trend of sensitization to BIT, analyse concomitant reactions, and identify patients with increased risk of BIT sensitization. METHODS: Retrospective analysis of data from 26 739 patients patch tested with BIT, sodium salt, 0.1% petrolatum as part of several special test series within the Information Network of Departments of Dermatology (IVDK), 2002 to 2021. RESULTS: Positive reactions to BIT were noted in 771 patients (2.9%). Sensitization frequency varied over time and increased in recent years, peaking at 6.5% in 2020. Painters and metalworkers handling metalworking fluids, but not cleaners, had a significantly increased risk of BIT sensitization. From our data, there is no evidence of immunological cross-reactivity between BIT and other isothiazolinones. CONCLUSION: The increasing frequency of sensitization justifies adding BIT to the baseline series. More research on the clinical relevance of positive patch test reactions to BIT and the cause for the rising numbers of BIT sensitization is needed.

Hypersensitivity to permanent tattoos: Literature summary and comprehensive review of patch tested tattoo patients 1997-2022.

We outline constituents of tattoo and permanent make-up ink with regard to inflammatory tattoo reactions and population-based confounders. The comprehensive review of patch-tested tattoo patients between 1997 and 2022 shows that tattoo allergy cannot be reliably diagnosed via patch testing with today's knowledge. Weak penetration and slow haptenization of pigments, unavailability of pigments as test allergens and a lack of knowledge concerning relevant epitopes hamper the diagnosis of tattoo allergy. Patch testing p-phenylenediamine and disperse (textile) dyes is not able to close this gap. Sensitization to metals was associated with all types of tattoo complications, although often not clinically relevant for the tattoo reaction. Binders and industrial biocides are frequently missing on ink declarations and should be patch tested. The pigment carbon black (C.I. 77266) is no skin sensitizer. Patch tests with culprit inks were usually positive with cheap ink products for non-professional use or with professionally used inks in patients with eczematous reactions characterized by papules and infiltration. Tape stripping before patch testing and patch test readings on Day 8 or 10 may improve the diagnostic quality. The meaningfulness of the categorical EU-wide ban of Pigment Green 7 and Pigment Blue 15:3 is not substantiated by the presented data.

Patch test results with the European baseline series, 2019/20-Joint European results of the ESSCA and the EBS working groups of the ESCD, and the GEIDAC.

BACKGROUND: Continual analyses of patch test results with the European baseline series (EBS) serve both contact allergy surveillance and auditing the value of included allergens. OBJECTIVES: To present results of current EBS patch testing, obtained in 53 departments in 13 European countries during 2019 and 2020. METHODS: Anonymised or pseudonymised individual data and partly aggregated data on demographic/clinical characteristics and patch test rest results with the EBS were prospectively collected and centrally pooled and analysed. RESULTS: In 2019 and 2020, 22 581 patients were patch tested with the EBS. Sensitization to nickel remained most common (19.8 [19.2-20.4]% positivity [95% confidence interval]). Fragrance mix I and Myroxylon pereirae yielded very similar results with 6.80 (6.43-7.19)% and 6.62 (6.25-7.00)% positivity, respectively. Formaldehyde at 2% aq. yielded almost one percentage point more positive reactions than 1% concentration (2.49 [2.16-2.85]% vs. 1.59 [1.33-1.88]); methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) and MI alone up to around 5% positives. Among the new additions, propolis was most commonly positive (3.48 [3.16-3.82]%), followed by 2-hydroxyethyl methacrylate (2.32 [2.0-2.68]%). CONCLUSION: Ongoing surveillance on the prevalence of contact sensitization contributes to an up-to-date baseline series containing the most frequent and/or relevant contact sensitizers for routine patch testing in Europe.

Contact sensitization to essential oils: IVDK data of the years 2010-2019.

BACKGROUND: Essential oils (EOs) are widely used in cosmetics, perfumes, massage fluids, aroma therapy and natural medicine. Some EOs contain contact sensitizers. OBJECTIVES: To describe the frequency of sensitization to EOs in dermatitis patients presenting in skin clinics including concomitant reactions, to evaluate the EO patch test preparations and to identify patient groups with an increased risk of EO sensitization. PATIENTS AND METHODS: Retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), 2010-2019. RESULTS: Twelve EOs were patch tested in an aimed manner in 10 930 patients, of whom 908 (8.3%) reacted to at least 1 EO. Only 6 EOs elicited more than 1% positive patch test reactions: ylang ylang (I + II) oil (3.9%), lemongrass oil (2.6%), jasmine absolute (1.8%), sandalwood oil (1.8%), clove oil (1.6%) and neroli oil (1.1%). Concomitant reactions among EOs or to EOs and fragrances were frequent. Among EO-positive patients, women, leg dermatitis patients, patients aged 40 years or more, masseurs and cosmeticians were over-represented. CONCLUSIONS: Sensitization to EOs occurs, albeit infrequently in most cases. Masseurs and cosmeticians have an increased risk of sensitization to EOs.

Pre-clinical assessment of SLN360, a novel siRNA targeting LPA, developed to address elevated lipoprotein (a) in cardiovascular disease.

BACKGROUND AND AIMS: The LPA gene encodes apolipoprotein (a), a key component of Lp(a), a potent risk factor for cardiovascular disease with no specific pharmacotherapy. Here we describe the pharmacological data for SLN360, a GalNAc-conjugated siRNA targeting LPA, designed to address this unmet medical need. METHODS: SLN360 was tested in vitro for LPA knockdown in primary hepatocytes. Healthy cynomolgus monkeys received single or multiple subcutaneous doses of the SLN360 sequence ranging from 0.1 to 9.0 mg/kg to determine the pharmacokinetic and pharmacodynamic effects. Liver mRNA and serum biomarker analyses were performed. RESULTS: In vitro, the SLN360 sequence potently reduces LPA mRNA in primary cynomolgus and human hepatocytes, while no effect was observed on the expression of APOB or PLG. In vivo, SLN360 exposure peaks 2 h after subcutaneous injection with near full elimination by 24 h. Specific LPA mRNA reduction (up to 91% 2 weeks after dosing) was observed with only the 3 mg/kg group showing appreciable return to baseline (40%). No consistent dose- or time-dependent effect on the expression of APOB, PLG or a panel of sensitive markers of liver lipid accumulation was observed. Potent (up to 95%) and long lasting (≥9 weeks) serum Lp(a) reduction was observed, peaking in all active groups at day 21. The minimally effective dose was determined to be 0.3 mg/kg with an ED50 of 0.6 mg/kg. CONCLUSIONS: SLN360 induces a sustained reduction in serum Lp(a) levels in cynomolgus monkeys following subcutaneous dosing. SLN360 has potential to address the unmet need of Lp(a) reduction in cardiovascular diseases.

European patch test results with audit allergens as candidates for inclusion in the European Baseline Series, 2019/20: Joint results of the ESSCAA and the EBSB working groups of the ESCD, and the GEIDACC.

BACKGROUND: In 2019, a number of allergens (haptens), henceforth, "the audit allergens," were considered as potential additions to the European Baseline Series (EBS), namely, sodium metabisulfite, 2-bromo-2-nitropropane-1,3-diol, diazolidinyl urea, imidazolidinyl urea, Compositae mix II (2.5% or 5% pet), linalool hydroperoxides (lin-OOH), limonene hydroperoxides (lim-OOH), benzisothiazolinone (BIT), octylisothiazolinone (OIT), decyl glucoside, and lauryl glucoside; Evernia furfuracea (tree moss), was additionally tested by some departments as well. OBJECTIVES: To collect further data on patch test reactivity and clinical relevance of the audit allergens in consecutive patients across Europe. METHODS: Patch test data covering the audit allergens in 2019 and 2020 were collected by those departments of the European Surveillance System on Contact Allergies testing these, as well as further collaborators from the EBS working group of the European Society of Contact Dermatitis (ESCD), and the Spanish Grupo Español de Investigación en Dermatitis de Contacto y Alergia Cutánea. As patch test outcome, reactions between day (D) 3 and D5 were considered. RESULTS: Altogether n = 12 403 patients were tested with any of the audit allergen. Positive reactions were most common to lin-OOH 1% pet. (8.74% [95%CI: 8.14-9.37%]), followed by lin-OOH 0.5% pet., and lim-OOH 0.3% pet (5.41% [95% CI: 4.95-5.89%]). Beyond these terpene hydroperoxides, BIT 0.1% pet. was the second most common allergen with 4.72% (95% CI: 4.2-5.28%), followed by sodium metabisulfite 1% pet. (3.75% [95%CI: 3.32-4.23%]) and Compositae mix 5% pet. (2.31% [95% CI: 1.84-2.87%]). For some allergens, clinical relevance was frequently difficult to ascertain. CONCLUSIONS: Despite many positive patch test reactions, it remains controversial whether lin- and lim-OOH should be tested routinely, while at least the two preservatives BIT and sodium metabisulfite appear suitable. The present results are a basis for further discussion and ultimately decision on their implementation into routine testing among the ESCD members.

The benefit of late readings in patch testing depends both on allergen and patient characteristics.

BACKGROUND: Patch test (PT) readings are recommended after 48 h and 72 h (D3). An additional day 7 (D7) reading has been suggested by some, although data on efficient patient selection are scarce. We investigated positive D7 reactions regarding (i) allergens in the baseline series and additional PT series of the German Contact Dermatitis Research Group (DKG) and (ii) characteristics of the patients tested. METHODS: Retrospective, multicentre analysis of 190 allergens derived from 17 DKG test series in 4687 patients with an additional D7 reading. Patients were patch tested with the baseline series and additional series, if required. Occurrence of novel D7 reactions as well as increasing skin reactions from D3 to D7 was analysed separately. RESULTS: Depending on the allergen tested, waiving D7 readings would have missed 4.4-26.8% of positive PT results. Patch test series with the highest number of novel D7 reactions were baseline series, metal series, and leather/shoe series. New positive reactions on D7 were associated with age over 50 years and with a negative irritant control containing sodium lauryl sulphate. Of note, application of the PT allergens for 48 h instead of 24 h was positively associated with late PT reactions. CONCLUSION: Within the most frequently tested allergens, without late readings, on average 11.7% of sensitizations would have been missed. Novel late reacting allergens were identified. This study comprehensively dissects patient-, allergen- and test-dependent parameters in support for D7 readings. We propose to always consider late readings individually based on effort-benefit considerations.

Occupational contact dermatitis in painters and varnishers: Data from the Information Network of Departments of Dermatology (IVDK), 2000 to 2019.

INTRODUCTION: Painters and varnishers ("painters") are exposed to various contact allergens and skin irritants, and therefore, are at risk for developing occupational dermatitis (OD). OBJECTIVE: To describe the spectrum of occupational sensitizations in painters and revise the corresponding current patch test recommendations. PATIENTS AND METHODS: Retrospective analysis of Information Network of Departments of Dermatology (IVDK) data from 2000 to 2019 with focus on male painters with OD, ages 20-59 years (n = 557) in comparison to age-matched male painters without OD (n = 422) and male OD patients who have had never worked as painters (n = 13 862). RESULTS: Male painters with OD have a significantly higher rate of allergic contact dermatitis and face dermatitis than male patients with OD who work in other professions. Positive patch tests to epoxy resin, methylisothiazolinone (MI), and methylchloroisothiazolinone (MCI)/MI were significantly more frequent in painters with OD than in the other groups. Epoxy resin sensitization was significantly associated with face dermatitis. CONCLUSIONS: Epoxy resin, MI, and MCI/MI represent the most important occupational sensitizers in painters. In addition to baseline, resins and glues, and industrial biocides series, the patients' own workplace materials should be tested in painters with suspected OD.